Pharmaceutical composition containing a combination of a statin and aspirin and method

ABSTRACT

A pharmaceutical composition is provided which is useful for cholesterol lowering and reducing the risk of a myocardial infarction, which includes a statin, such as pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin or fluvastatin, in combination with aspirin, in a manner to minimize interaction of aspirin with the statin and minimize side effects of aspirin. A method for lowering cholesterol and reducing risk of a myocardial infarction employing such composition is also provided.

FIELD OF THE INVENTION

[0001] The present invention relates to a pharmaceutical compositionwhich includes a statin cholesterol lowering agent and aspirin in amanner to minimize interaction of aspirin with the statin, for use inlowering cholesterol and reducing risk of a myocardial infarction, andto a method for lowering cholesterol and reducing risk of a myocardialinfarction employing such composition.

BACKGROUND OF THE INVENTION

[0002] The use of aspirin for reducing the risk of a myocardialinfarction and the use of statins for lowering cholesterol andpreventing or treating atherosclerosis and cardiovascular disease andcerebrovascular disease are well documented. In fact, it is not uncommonthat patients having elevated cholesterol levels who are at high riskfor a myocardial infarction take both a statin and aspirin. However, useof both a statin and aspirin may require special care to insure thatdrug interaction, including physical and chemical incompatibility, andside effects, are kept to a minimum while achieving maximum benefit fromthese drugs.

[0003] With regard to possible drug interaction, aspirin is an acid,while some of the statins, such as pravastatin, atorvastatin andcerivastatin, are alkali salts. Thus, mixing of such statins (alkalisalts) with aspirin could result in aspirin hydrolysis as well as statindegradation. Pravastatin, on the other hand, is also a very acid labilecompound. When pravastatin and aspirin are combined, the aspirin couldcause pravastatin degradation which could result in lowerbioavailability of pravastatin.

[0004] Aspirin is known for causing gastrointestinal bleeding when usedfor long-term therapy. It is therefore desirable in long-term aspirintherapy that the aspirin be provided in a form which minimizes sideeffects.

[0005] In view of the above, it is seen that there is a long-felt wantin patients required to take both a statin and aspirin for astatin-aspirin formulation which provides for maximum cholesterollowering and reduction of risk of a myocardial infarction without theundesirable side effects and drug interaction normally associated withuse of such combination.

DESCRIPTION OF THE INVENTION

[0006] In accordance with the present invention, a pharmaceuticalcomposition is provided which includes a statin cholesterol loweringagent and aspirin, which provides for maximum patient benefits includingmaximum cholesterol lowering and reduced risk of a myocardial infarctionwith minimal physical and chemical incompatibility (including minimalstatin:aspirin interaction), and reduced side effects normallyassociated with use of such drugs.

[0007] In addition, in accordance with the present invention, a methodis provided for lowering serum cholesterol, preventing or inhibiting ortreating atherosclerosis, and/or reducing risk of or treating acardiovascular event or disease including coronary artery disease andcerebrovascular disease, wherein a pharmaceutical composition containinga combination of a statin cholesterol lowering agent and aspirin in asingle dosage form, in a manner so as to minimize interaction of thestatin and aspirin, is administered to a patient in need of treatment.

[0008] Preferred pharmaceutical compositions of the present inventionmay take the form of several different embodiments. Thus, in oneembodiment of the present invention, a pharmaceutical composition isprovided wherein the statin (including any statin cholesterol loweringagent) and aspirin are formulated together in a single tablet. Thetablet of the invention is preferably in the form of a bilayered tabletwhich includes a first layer and a second layer. Aspirin, in the form ofgranules of preselected size will be present in the first layer togetherwith optional excipients as described hereinafter, while the statin willbe present in the second layer which optionally may include one or morebuffering agents (as necessary to prevent undesirable statin/aspirininteraction) and optionally one or more excipients as describedhereinafter.

[0009] In addition, the bilayered tablet of the invention may include anouter protective coating or finishing layer as described hereinafter.

[0010] Another embodiment of the present invention comprises a coredtablet which includes a core and a buffering layer or outer coat whichcan be compressed onto the core as a dry coat. The core will preferablyinclude compressed aspirin granules while the buffering layer or outercoat will include a statin (including any statin cholesterol loweringagent) together with one or more buffering agents and optionalexcipients.

[0011] Provision of aspirin in the core and statin in the bufferinglayer will effectively reduce the aspirin side effects and also minimizedrug incompatibilities while providing maximum efficacy.

[0012] The so-described cored tablet may also optionally include anouter protective coating or finishing layer as described hereinafter.

[0013] In addition, in accordance with the present invention, apharmaceutical composition is provided which is in the form of a tabletor capsule which includes a mixture of aspirin granules having anenteric coating and particles or granules of a statin. Such acombination will provide maximum efficacy while minimizing side effectsresulting from prolonged aspirin therapy.

[0014] In the above embodiment containing enteric coated aspirin, thestatin may include any statin cholesterol lowering agent, but preferablyis simvastatin, lovastatin or cerivastatin.

[0015] In yet another embodiment of the pharmaceutical composition ofthe present invention, enteric coated aspirin granules as describedabove may be further coated with a protective coating or finishinglayer. The double coated particles of aspirin can be mixed with anystatins such as pravastatin, atorvastatin, simvastatin, lovastatin, andcerivastatin powders or granules, and the mixture can be encapsulated ortableted as described herein. In such case, further coating of theenteric coated aspirin particles is desired to minimize interaction ofalkaline pravastatin, atorvastatin or cerivastatin with enteric coatedaspirin. This combination will protect the integrity of the enteric coatand minimize the side effects normally resulting from prolonged aspirintherapy. The aspirin and the statin granules do not need to be mixedtogether; these can even be encapsulated separately into the samecapsule shells in two shots.

[0016] Another embodiment of the pharmaceutical composition of theinvention includes granules of enteric coated aspirin and enteric coatedstatin (including any statin cholesterol lowering agent), in the samedosage form such as compressed tablets or capsules.

[0017] The tablets containing the enteric coated granules of aspirin andstatin may also include an outer protective coating or finishing layer.

[0018] In a further embodiment of the pharmaceutical composition of theinvention, where aspirin side effects are not an issue, for example,where low dose aspirin is present (81 mg or less), the composition ofthe invention may comprise a mixture of aspirin granules and statin(including any statin cholesterol lowering agent, preferably,simvastatin, lovastatin or enteric coated particles of pravastatin orparticles of pravastatin, atorvastatin and cerivastatin containing anouter protective coating or finishing layer); the above mixture may takethe form of compressed tablets or capsules (where the mixture can beencapsulated separately in two shots in the same capsule shells).

DETAILED DESCRIPTION OF THE INVENTION

[0019] The pharmaceutical composition of the invention which includes acombination of a statin and aspirin is effective in preventing, reducingand/or treating elevated cholesterol levels (such as inhypercholesterolemia), atherosclerosis, cardiovascular events anddisease including coronary events and cerebrovascular events, andcoronary artery disease and/or cerebrovascular disease.

[0020] The terms “cardiovascular event(s)” and “cardiovascular disease”as employed herein refer to coronary and/or cerebrovascular event(s) anddisease including primary myocardial infarction, secondary myocardialinfarction, myocardial ischemia, angina pectoris (including unstableangina), congestive heart failure, sudden cardiac death, cerebralinfarction, cerebral thrombosis, cerebral ischemia, transient ischemicattack and the like.

[0021] The term “coronary artery disease” (CAD) as employed hereinrefers to diseases including atherosclerosis of the coronary arteries,previous myocardial infarction, ischemia, angina pectoris and/or heartfailure.

[0022] The term “cerebrovascular disease” as employed herein refers todiseases including atherosclerosis of the intracranial and/orextracranial arteries, cerebral infarction, cerebral thrombosis,cerebral ischemia, stroke, and/or transient ischemic attacks.

[0023] Aspirin will preferably be employed in the form of salicylic acidacetate also referred to as acetylsalicylic acid.

[0024] The pharmaceutical composition of the invention in the form of atablet or capsule will include aspirin in amounts from about 10 to about800 mg, preferably 50 to about 650 mg.

[0025] The aspirin for use in forming the pharmaceutical composition ofthe invention will preferably be in the form of granules having anaverage particle size within the range from about 10 μm to about 2 mm,more preferably from about 0.25 mm to about 1.0 mm.

[0026] Statin cholesterol lowering agents suitable for use herein willinclude HMG CoA reductase inhibitors such as pravastatin, lovastatin,simvastatin, atorvastatin, fluvastatin, cerivastatin and other statinssuch as fluindostatin and preferably pravastatin, simvastatin,atorvastatin or cerivastatin.

[0027] The pharmaceutical composition of the invention will contain astatin such as pravastatin, lovastatin, simvastatin, atorvastatin,fluvastatin or cerivastatin in an amount as normally employed for suchstatin as exemplified in the 52nd edition of the Physician's DeskReference (PDR) (1998). Thus, depending upon the particular statin, itmay be employed in amounts within the range from about 0.1 mg to 2000 mgper day in single or divided doses, and preferably from about 0.2 toabout 200 mg per day. Most preferably for pravastatin, a daily dosage of10 to 40 mg may be employed; for lovastatin, a daily dosage of 10 to 80mg may be employed, for simvastatin a daily dosage of 5 to 40 mg may beemployed; for atorvastatin, a daily dosage of 10 to 80 mg may beemployed, for fluvastatin, a daily dosage of 20 to 80 mg may beemployed; and for cerivastatin, a daily dosage of 0.2-0.3 mg may beemployed.

[0028] In forming the pharmaceutical composition of the invention in theform of a bilayered tablet, the first layer containing aspirin will alsopreferably include bulking agents such as lactose, microcrystallinecellulose, wood cellulose, corn starch, modified corn starch, calciumphosphate, sugar, dextrose, mannitol or sorbitol. The bulking agent willbe present in an amount from about 1 to about 90%, preferably from about5 to about 85% by weight of the first layer containing aspirin.

[0029] The first layer may also include a tabletting lubricant, such aszinc stearate, magnesium stearate, calcium stearate, talc, carnauba wax,stearic acid, palmitic acid or hydrogenated vegetable oils and fats, inan amount within the range from about 0.01 to about 4%, and preferably0.02 to about 2% by weight of the first layer.

[0030] The second layer of the bilayered tablet containing statincholesterol lowering agent will usually include a bulking agent such aslactose, microcrystalline cellulose, modified corn starch, calciumphosphate or other bulking agent as set out above for the first layer,in an amount within the range from about 1 to about 90%, preferably fromabout 5 to about 85% by weight of the second layer. In addition, thesecond layer may include a binder such as corn starch, pregelatinizedstarch, polyvinyl pyrrolidone (PVP), hydroxypropylmethyl cellulose(HPMC), ethyl cellulose, cellulsoe acetate and the like, in an amountwithin the range from about 0.5 to about 20%, preferably from about 1 toabout 10% by weight of the second layer, and a tabletting lubricant suchas magnesium stearate, zinc stearate, or other lubricant as set outabove with respect to the first layer in an amount from about 0.01 toabout 4%, preferably from about 0.02 to about 2% by weight of the secondlayer.

[0031] The buffering agents present in the second layer may includeconventional acid buffers such as calcium carbonate, magnesium oxide,magnesium carbonate, magnesium hydroxide, aluminum hydroxide,dihydroxyaluminum sodium carbonate, aluminum magnesium hydroxide sulfateor aluminum hydroxide magnesium carbonate co-dried gel, or mixtures ofone or more thereof, in amounts as needed to insure that the aspirinwill be sufficiently buffered to inhibit GI side effects. Thus, amountsof buffering agent within the range from about 10 to about 1000 mg,preferably from about 50 to about 500 mg will be employed depending uponthe amount of aspirin present in the first layer.

[0032] In forming the bilayered tablet of the invention, the first layercontaining aspirin may be prepared by conventional wet granulation ordry granulation (compaction) techniques.

[0033] The second layer containing statin and buffers may be prepared byconventional wet granulation or dry granulation (compaction) techniques.

[0034] The first and second layers may then be compressed and combinedto form a bilayered tablet employing conventional bilayer tablettingequipment.

[0035] Other conventional ingredients which may optionally be present ineither of the two layers include preservatives, stabilizers,anti-adherents or silica flow conditioners or glidants, such as Syloidbrand silicon dioxide as well as antioxidants such as Vitamin E, VitaminC, and folic acid, Vitamin B₆ and Vitamin B₁₂.

[0036] The bilayer tablet of the invention may also include an outerprotective coating layer which may comprise from 0 to about 15% byweight of the bilayer tablet. The outer protective coating layer whichis applied over the bilayered tablet may comprise any conventionalcoating formulations and will include one or more film-formers orbinders, such as a hydrophilic polymer like hydroxypropylmethylcellulose (HPMC) and a hydrophobic polymer like ethyl cellulose,cellulose acetate, polyvinyl alcohol-maleic anhydride copolymers,acrylic copolymers, β-pinene polymers, glyceryl esters of wood resinsand the like, and one or more plasticizers, such as polyethylene glycol,triethyl citrate, diethyl phthalate, propylene glycol, glycerin, butylphthalate, castor oil and the like.

[0037] The film formers are applied from a solvent system containing oneor more solvents including water, alcohols like methyl alcohol, ethylalcohol or isopropyl alcohol, ketones like acetone, or ethylmethylketone, chlorinated hydrocarbons like methylene chloride,dichloroethane, and 1,1,1-trichloroethane.

[0038] The pharmaceutical composition of the invention in the form of acored tablet wherein the aspirin forms the core, and statin plusbuffering agent are present in a surrounding coat layer, may be preparedemploying conventional cored tablet technology. Thus, the aspirincontaining core (including excipients and other ingredients as describedfor the first layer in the bilayered tablet of the invention) may beformed in a manner similar to the first layer of the bilayered tablet asdescribed hereinbefore. The buffering layer containing statin as well asexcipients and other ingredients (as described hereinbefore for thesecond layer of the bilayered tablet of the invention) may be compressedonto the core as a dry coat.

[0039] The so-formed cored tablet may be coated with an outer protectivecoating layer as described above for the bilayered tablet.

[0040] Another embodiment of the pharmaceutical composition of theinvention is formed of tablets or capsules containing a mixture ofenteric coated aspirin granules, and a statin such as lovastatin,simvastatin or cerivastatin, which may be in the form of a tablet orcapsule.

[0041] The aspirin granules can be coated with conventional entericpolymers coatings in aqueous or non-aqueous systems. For example,Eudragit L-30D-55 (acrylic acid copolymers-Rohm Pharma) (5 to 25%solids) containing 10 to 15% of diethylphthlate (w/w) as plasticizer canbe used in an aqueous system.

[0042] Other conventional enteric polymer coating systems may beemployed such as Eudragit R and S series resins, (acrylic acidcopolymers-Rohm Pharma), cellulose acetate phthalate, cellulose acetatemaleate, cellulose acetate succinate, hydroxypropylmethyl cellulosephthalate, hydroxypropylmethylcellulose acetate succinate, and the like,and a suitable plasticizer such as triethyl citrate, diethyl phthalate,tributyl citrate, triacetin, dibutyl phthalate dibutyl sebicate, Myvacet940, and other commonly used plasticizers as may be suitable forparticular enteric polymers can be used. It will be appreciated that anypolymer with suitable plasticizer can be used in aqueous or non-aqueoussystem to form an enteric coating on the aspirin granule or particle.

[0043] In another embodiment of the pharmaceutical composition of theinvention, the enteric coated aspirin granules described above may befurther coated with an outer protective finishing coat or layer asdescribed hereinbefore.

[0044] The double coated aspirin granules can be mixed with a statinsuch as pravastatin, atorvastatin, simvastatin, lovastatin, fluvastatinor cerivastatin powders or granules and the mixture can be encapsulatedor tableted as described above.

[0045] In yet another embodiment of the pharmaceutical composition ofthe invention, aspirin is enteric coated as described above and thestatin (pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatinand cerivastatin) can optionally be enteric coated. The statins can becoated in the form of pure drugs or after spheronization oragglomeration. The particles for coating do not need to be perfectlyspherical. These could be rods or irregular particles. The entericcoated particles of the two drugs (aspirin and statin) can be tabletedor encapsulated together. As described above, appropriate excipients(fillers, binders, disintegrants, and lubricant, etc.) can be used tofacilitate tabletting. This statin:aspirin combination will minimizeside effects of aspirin, and eliminate chemical incompatibility.

[0046] If, aspirin side effects are not an issue, especially at lower(e.g., 80 mg) aspirin dosages, then aspirin granules (including uncoatedaspirin) can be mixed with simvastatin, lovastatin and fluvastatinpowder or granules for tabletting or for encapsulating.

[0047] In yet another embodiment, aspirin granules can be mixed withenteric coated particles of pravastatin, cerivastatin and atorvastatinand the mixture can be tableted or encapsulated or the two granules canbe encapsulated in two shots in the same capsule shells.

[0048] In carrying out the method of the present invention, thepharmaceutical composition of the invention containing the combinationof the statin cholesterol lowering drug and aspirin may be administeredto mammalian species, such as monkeys, dogs, cats, rats, humans, etc.,and, as described hereinbefore, may be incorporated in a tablet orcapsule. The above dosage forms will also include the necessary carriermaterial, excipient, lubricant, buffer, antibacterial, bulking agent(such as mannitol), antioxidants such as Vitamin C and Vitamin E, aswell as Vitamin B₆, Vitamin B₁₂, folic acid, sodium bisulfite, and thelike.

[0049] The dose administered must be adjusted according to age, weightand condition of the patient, as well as the route of administration,dosage form and regimen and the desired result.

[0050] The compositions described above may be administered in thedosage forms as described above in single or divided doses of one tofour times daily. It may be advisable to start a patient on a low dosecombination and work up gradually to a high dose combination.

[0051] Tablets of various sizes can be prepared, e.g., of about 2 to2000 mg in total weight, containing the active substances in the rangesdescribed above, with the remainder being a physiologically acceptablecarrier of other materials according to accepted pharmaceuticalpractice. These tablets can, of course, be scored to provide forfractional doses in some cases. Gelatin capsules can be similarlyformulated.

[0052] Liquid formulations can also be prepared by dissolving orsuspending one or the combination of active substances in a conventionalliquid vehicle acceptable for pharmaceutical administration so as toprovide the desired dosage in one to four teaspoonsful.

[0053] Such dosage forms can be administered to the patient on a regimenof one to four doses per day.

[0054] In general, formulating the compositions, as described herein,the active substances, in the amounts described above, are compounded asdescribed herein (according to accepted pharmaceutical practice) with aphysiologically acceptable vehicle, carrier, excipient, binder,preservative, stabilizer, flavor, etc., in the particular type of unitdosage form.

[0055] Illustrative of the excipients which may be incorporated intablets are the following: a binder such as gum tragacanth, acacia, cornstarch or gelatin; an excipient such as dicalcium phosphate orcellulose; a disintegrating agent such as corn starch, potato starch,alginic acid, sodium starch glycolate or the like; a lubricant such asstearic acid, zinc stearate or magnesium stearate; a sweetening agentsuch as sucrose, aspartame, lactose or saccharin; a flavoring agent suchas orange, peppermint, oil of wintergreen or cherry. When the dosageunit form is a capsule, it may contain in addition to materials of theabove type a liquid carrier such as a fatty oil. As indicated, variousother materials may be present as coatings or to otherwise modify thephysical form of the dosage unit. For instance, tablets or capsules maybe coated with shellac, sugar or both. A syrup of elixir may contain theactive compounds, water, alcohol or the like as the carrier, glycerol assolubilizer, sucrose as sweetening agent, methyl and propyl parabens aspreservatives, a dye and a flavoring such as cherry or orange.

[0056] Some of the active substances described above form commonlyknown, pharmaceutically acceptable salts such as alkali metal and othercommon basic salts or acid addition salts, etc. References to the basesubstances are therefore intended to include those common salts known tobe substantially equivalent to the parent compound.

[0057] The formulations as described above will be administered for aprolonged period, that is, for as long as the potential forcardiovascular events and disease including coronary artery diseaseand/or cerebrovascular disease remains or the symptoms continue.Sustained release forms of such formulations which may provide suchamounts daily, biweekly, weekly, monthly and the like may also beemployed. A dosing period of at least 10 days are required to achieveminimal benefit.

[0058] The following Examples represent preferred embodiments of thepresent invention.

[0059] Formulations suitable for oral administration are prepared asdescribed below.

EXAMPLE 1

[0060] A bilayered tablet containing aspirin in a first layer andpravastatin in a second layer as described below may be prepared asfollows. General Formula: Amount or % First Layer: in First LayerAspirin granulation 80 mg-325 mg Lactose/microcrystalline qs Cellulosegranulation* Zinc Stearate 0.1%-0.5    Amount in Second Second Layer:Layer Calcium Carbonate 50 mg-250 mg Magnesium Oxide 50 mg-100 mgMagnesium Carbonate 25 mg-50 mg  Corn Starch 25 mg-50 mg  Pravastatin 20mg-40 mg  Magnesium stearate 0.2%-0.5%

[0061] Procedure:

[0062] The aspirin granulation in the first layer is blended withsufficient quantity of the lactose/microcrystalline cellulosegranulation as necessary to bulk up in order to have sufficientgranulation to compress a satisfactory layer. The aspirin granules alongwith the bulking granules are blended with zinc stearate as a lubricant.Zinc stearate can be replaced with other non-alkaline lubricants, i.e.,Lubritab® or other high melting point hydrogenated powdered waxes.

[0063] Ingredients in the second layer are wet granulated using starchpaste or other wet granulating materials, for example, PVP or HPMC, orcan be dry granulated by compaction. The granules can be sized andlubricated. The two tablet layers are compressed using appropriateconventional tools and a suitable bilayer tabletting press, to form thebilayered tablet of the invention.

[0064] The quantity of the buffering agents used in the second layer canbe adjusted as necessary to minimize gastrointestinal side effects. Itshould be understood that these buffering agents can be replaced withother suitable buffering agents, if desired.

[0065] The so-formed bilayered tablets may be coated with HPMC(hydroxypropylmethylcellulose) or commercially available Opadry® clearor Dri Klear® (HPMC) or any of these with any desired color. This coatis not limited to HPMC based coats only. Polymers, i.e., Eudragit E30D(acrylic acid copolymer) and others can also be used to give the tabletsa finishing coat. Coating Formula (example): Opadry ® clear 10%-30%Purified water qs

[0066] Procedure:

[0067] Opadry® is dispersed in water to prepare a dispersion of 10%-30%solids*. This dispersion is used for coating the above tablets usingconventional coating equipment. The coating of 0.2%-2% or any desiredlevel (based on the weight of the finished coated bilayered tablet) canbe applied to the bilayered tablet employing conventional techniques.

[0068] The so-formed tablets provide maximum benefits while minimizingdrug interaction and other undesirable side effects.

[0069] It will be understood that pravastatin contained in the bufferedlayer of the bilayered tablet of the invention may be replaced withequivalent cholesterol lowering amounts of simvastatin, lovastatin,atorvastatin, cerivastatin or fluvastatin.

EXAMPLE 2

[0070] Tablets or capsules containing enteric coated aspirin and astatin, which preferably is simvastatin, lovastatin or cerivastatin,having the following composition are prepared as described below.General Formula: Aspirin particles 80 mg-325 mg Eudragit L-30D-55 qsDiethyl Phthalate qs Statins (simvastatin, lovastatin, Desired Dose (asor cerivastatin) per PDR)

[0071] Procedure:

[0072] Aspirin particles are coated with enteric polymers in aqueous ornon-aqueous systems. Eudragit L-30D-55 containing 10%-15% of diethylphthalate (w/w) is used in an aqueous system. The coating suspension isprepared having solid contents of 10%-30%.

[0073] To prepare the coating suspension, diethyl phthalate is added tothe Eudragit L-30D-55 and the contents stirred till diethyl phthalate iscompletely dissolved. This is diluted with water to obtain thesuspension with desired solid contents. Using this enteric coatingsuspension, the aspirin particles are coated in a fluid bed coatingsystem using a Wurster insert or with top spray coating, so that aspirinparticles of enteric quality can be produced. The enteric coatedparticles are mixed with statin powders or granules and the mixtures areencapsulated or tableted using appropriate excipients (fillers, binder,disintegrants, and lubricants). Any of the listed statin can be selectedat its desired dose level along with the desired aspirin dose.

[0074] The statins can also be granulated, and the statin granules andthe enteric coated aspirin granules can be filled separately into thesame capsule shell. Statin granules can be prepared by dry or wetgranulation processes, using suitable conventional excipients as is wellknown in the pharmaceutical field.

[0075] The above formulations provide maximum benefit while minimizingundesirable side effects and incompatibilities.

EXAMPLE 3

[0076] A cored tablet containing an aspirin core and a buffered coatingthereon containing a statin having the following composition is preparedas described below. General Formula: Amount or % Core Layer: in CoreLayer Aspirin granulation 80 mg-325 mg Lactose/microcrystalline qsCellulose granulation* Zinc Stearate 0.1%-0.5    Amount in Second OuterLayer: Layer Calcium Carbonate 50 mg-250 mg Magnesium Oxide 50 mg-100 mgMagnesium Carbonate 25 mg-50 mg  Corn Starch 25 mg-50 mg  Pravastatin 20mg-30 mg  Magnesium stearate 0.2%-0.5% Filler/Binder** qs # also do notcontain excessive moisture and are compatible with aspirin granules.These bulking granules must have enough compatibility to allowcompression of two layer tablets).

[0077] Procedure:

[0078] The aspirin granulation for the core is blended with sufficientquantity of the lactose/microcrystalline cellulose granulation asnecessary to bulk up in order to have sufficient granulation to compressa satisfactory core. The aspirin granules along with the bulkinggranules are blended with zinc stearate as a lubricant. Zinc stearatecan be replaced with other non-alkaline lubricants, i.e., Lubritab® orother high melting point hydrogenated powdered waxes.

[0079] Ingredients for the outer layer are wet granulated using starchpaste or other wet granulating materials, for example, PVP or HPMC, orcan be dry granulated by compaction. The granules can be sized andlubricated. The dry coated tablets can be compressed using appropriatetools and a suitable dry coating tabletting press.

[0080] The quantity of the buffering agents used in the outer layer canbe adjusted as in Example 1. Other known buffering agents may be used aswell.

What is claimed is:
 1. A pharmaceutical composition comprising a statincholesterol lowering agent and aspirin in a formulation designed tominimize statin:aspirin interaction.
 2. The pharmaceutical compositionas defined in claim 1 wherein the statin and aspirin are formulatedtogether in the same dosage formulation.
 3. The pharmaceuticalcomposition as defined in claim 2 wherein the statin and aspirin areformulated together in a single tablet.
 4. The pharmaceuticalcomposition as defined in claim 3 wherein the tablet is a bilayeredtablet wherein the aspirin is present in a first layer, and the statinis present in a second layer.
 5. The pharmaceutical composition asdefined in claim 4 wherein the layer containing the statin also includesone or more buffering agents.
 6. The pharmaceutical composition asdefined in claim 3 wherein the tablet includes a core and a coatinglayer surrounding said core and wherein one of the statin and aspirin ispresent in the core and the other is present in the coating layersurrounding the core.
 7. The pharmaceutical composition as defined inclaim 6 wherein the aspirin is present in the core and the statin ispresent in the coating layer.
 8. The pharmaceutical composition asdefined in claim 7 wherein the coating layer also includes one or morebuffering agents.
 9. The pharmaceutical composition as defined in claim1 wherein the statin is pravastatin, lovastatin, simvastatin,fluvastatin, atorvastatin or cerivastatin.
 10. The pharmaceuticalcomposition as defined in claim 1 further including one or morebuffering agents in combination with the statin.
 11. The pharmaceuticalcomposition as defined in claim 3 further including an outer protectivecoating or finishing layer surrounding said tablet.
 12. Thepharmaceutical composition as defined in claim 1 wherein the aspirin isin the form of enteric coated aspirin granules.
 13. The pharmaceuticalcomposition as defined in claim 12 in the form of tablets or granulescontained in a capsule.
 14. The pharmaceutical composition as defined inclaim 12 wherein the enteric coated aspirin granules include a finishingovercoat, and the coated aspirin and statin are in the form of a tabletor capsule.
 15. The pharmaceutical composition as defined in claim 14wherein the coated aspirin granules and statin granules are encapsulatedseparately into the same capsule shells.
 16. The pharmaceuticalcomposition as defined in claim 2 wherein the aspirin is in the form ofenteric coated granules of aspirin and the statin is in the form ofenteric coated granules of statin, in the form of compressed tablets orcapsules.
 17. The pharmaceutical composition as defined in claim 1 inthe form of a tablet or capsule containing both aspirin granules andstatin granules.
 18. The pharmaceutical composition as defined in claim17 wherein the statin is in the form of enteric coated statin granules.19. The pharmaceutical composition as defined in claim 17 wherein thestatin granules include an outer protective coating to minimizeinteraction with aspirin.
 20. The pharmaceutical composition as definedin claim 1 in the form of a bilayered tablet which comprises a firstlayer comprising aspirin granules and one or more excipients, and asecond layer comprising a statin and one or more buffering compounds andone or more excipients.
 21. The pharmaceutical composition as defined inclaim 20 wherein the first layer comprises aspirin granules, one or morebulking agents and optionally a lubricant, and the second layercomprises a statin, optionally a wet granulating agent, one or morebuffering compounds selected from the group consisting of calciumcarbonate, magnesium oxide, magnesium carbonate and mixtures thereof,and optionally magnesium stearate.
 22. The pharmaceutical composition asdefined in claim 20 further including an outer protective coatingsurrounding said bilayered tablet.
 23. The pharmaceutical composition asdefined in claim 1 further including an antioxidant.
 24. Thepharmaceutical composition as defined in claim 23 wherein theantioxidant is vitamin C and/or vitamin E.
 25. A method for loweringserum cholesterol or preventing or inhibiting or treatingatherosclerosis or reducing risk of or treating a cardiovascular eventor desease, coronary artery disease or cerebrovascular disease, whichcomprises administering to a patient in need of treatment atherapeutically effective amount of a pharmaceutical compositioncomprising a combination of a statin cholesterol lowering agent andaspirin in a single dosage form, which dosage form minimizes interactionbetween the statin and aspirin, and reduces the side effects of aspirin.26. The method as defined in claim 25 wherein the statin employed ispravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin orcerivastatin.